Medical-grade blister-packaging films protect prescription and over-the-counter drugs against moisture and other environmental factors. Such films must thermoform easily and be compatible with commercially available lidding materials. A blister pack-ageï¿½s ability to limit water-vapor permeation depends on the polymer used. It also depends on having a consistent distribution of material throughout the blister cavity. If material distribution is uneven, water vapor may pass through thin areas of the blister and reduce product shelf life.

Although many thermoformable films are used in pharmaceutical blister packages, those made with polyvinyl chloride (PVC) are most common. A drawback of PVC is that some consumers perceive it as posing environmental risks. Given this, Procter & Gamble Pharmaceuticals began a development program to investigate alternative film options.The lead film selected as an alternative to PVC was cyclic olefin copolymer (COC). COC received FDA approval in November 2002 for the Actonel 35-mg blister package. This was the first FDA approval for a drug packaged in a COC-containing film. The COC film used Klï¿½ckner Pentaplastï¿½s Pentapharm COC 240 P/03 film, which has 30-ï¿½m polypropylene (PP) outer layers and a 240-ï¿½m core of Topas COC from Ticona.

Procter & Gamble chose the COC-based film after considering available blister-film options, including PVC, polyethylene terephthalate (PET), and PP.

COC is a viable alternative to PVC. Its flat films are nearly 10 times less permeable to water vapor than PVC films. They are also less controversial environmentally since they are halogen-free. COC has a low water-vapor transmission rate (WVTR) in films as thin as 100 ï¿½m. A 250 ï¿½m-thick COC multilayer film, for example, has a permeability of 0.29 g/m2/day, a value that cannot easily be achieved with PET, PP, or low-grade PVdC-coated PVC films (see Table I). COC absorbs less than 0.01% moisture (see Table II).

COC creates clear, colorless films that thermoform easily on existing machines at temperatures comparable to those used for PVC. It complies with EP, JP, and USP Class VI certification and has FDA drug and device master files. Relatively inert, it resists hydrolytic degradation, acids, alkalis, and all polar solvents, which minimizes the likelihood that it will react with the contents of a blister package.

Table II. COC properties (click to enlarge).

COC is typically used as the core layer in coextruded or three-layer laminated films. Outer layers can be made of PP, PVC, or PVdC. The COC core is typically 120, 190, 240, or 300-ï¿½m thick and is sandwiched between 20- to 30-ï¿½m outer layers, according to the existing guidelines of VDMA 8747. (VDMA 8747 specification offers minimum criteria for assessing the quality of films and foils used to manufacture blister packs for drugs. This specification was revised in 2002 to include COC films.) The outer layers increase film impact and tensile strength, flexibility, and grease resistance. They also allow the use of available sealing systems and can reduce the risk of drug product interaction.

COCï¿½s transparency makes blister cards aesthetically pleasing. It has good stiffness and its elongation-at-break of 5 to 10% helps it withstand the rigors of the forming process and the stress of being pulled through the machine. This polymer has a wide processing window. It is typically thermoformed at 120ï¿½ to 150ï¿½C, depending on the equipment used, which is comparable to that needed with PVC. It can be processed on existing thermoforming machines with little adjustment and without the need for anticorrosive agents.

COC is an economical alternative to other blister-packaging films. Its cycle time is 10 to 20% less than that of PVC/PVdC film. It also has low density. For example, it is 40% less dense than PVC (1.0 g/cm3 versus 1.4 g/cm3), so it yields more film per pound of resin than PVC. Also, a thinner layer of COC can be used for the same barrier effect as PVC.

Experimental COC Trials

To evaluate the machinability of COC film, Procter & Gamble conducted several experimental trials on a development-scale Klï¿½ckner Medipack EAS II form-fill-seal machine. During the trials, the films were preheated by contact plates on both sides of the web. The softened film was drawn into a multicavity female mold and shaped into small cavities by air pressure. After forming, the blisters were cooled via chilled rails set to 15ï¿½C. The blisters were then heat-sealed to foil that had a heat-seal coating compatible with the blister material.

Table III. Critical operating variables (click to enlarge).

In evaluating the new COC film, Procter & Gamble ran tests using a 300-ï¿½m film having a 240-ï¿½m COC core and 30-ï¿½m PP outer layers. The blister cards were evaluated for wall thickness uniformity, card curl, seal integrity, and WVTR.

The company identified three critical variables for the equipment used: forming temperature, forming pressure, and sealing temperature. It executed a formal design of experiments based on the high and low settings for each of the three variables. The acceptable operating window was determined to be 129ï¿½ to 147ï¿½C for forming temperature, 40 to 60 psi for forming pressure, and 168ï¿½ to 185ï¿½C for sealing temperature. Machine speed (35 strokes/min), forming timing (200ï¿½C on, 305ï¿½C off), and cooling temperature (15ï¿½C) were held constant.

An evaluation of the blister cards from each experiment showed that card curl was insignificant across the range of values for the three variables and all cards were well sealed. Data on blister wall thickness uniformity were collected from each run. WVTR testing was performed on five blister cavities from the experiment having the most uniform blister wall thicknesses. WVTR averaged 0.00188 g/pkg/day at 38ï¿½C and 100% relative humidity.

The company then tested the COC film for compatibility with three types of foil, each from a different supplier. Blister cards were made by varying the sealing-temperature range while holding all other variables constant (forming temperature at 138ï¿½C, forming pressure at 50 psi, and speed at 35 strokes/min). The sealing-temperature range for two of the three foils was 160ï¿½ to 190ï¿½C, while the third had a sealing temperature range of 168ï¿½ to 185ï¿½C. Further testing showed all blister cards were well sealed, and card curl was acceptable.

PVC blister cards were made from Klï¿½ckner Pentaplastï¿½s M570/01 (previously PH170/01) 250-ï¿½m blister film and Alcan 25-ï¿½m hard-tempered aluminum foil. All cards were made on a Klï¿½ckner Medipack EAS II blister machine (see Table III for critical variables). Both large and small blister cavities had relatively uniform wall thickness for COC and PVC.

WVTR data were collected on the COC and PVC blister cards. The results showed that the COC film had 78.8% less WVTR than PVC in smaller cavities and 79.5% in the large ones (see Table IV). All cards had good heat-seal integrity. Card curl testing showed no difference between the PVC and COC.

Commercial-Scale Comparison

Several test runs compared COC and PVC blister packages produced on commercial-scale form-fill-seal equipment. Both qualitative and quantitative data were generated during the tests. Klï¿½ckner Medipak, a Procter & Gamble pharmaceutical packaging plant, and a contract packager conducted the tests.

Klï¿½ckner Medipak found the two films to be interchangeable. The company determined that the two films had similar scrap rates, reliability, and quality. It noted that COC blister packages could be produced at slightly lower forming and sealing temperatures and faster line speeds. To show that the two films were interchangeable, Klï¿½ckner Medipak switched from PVC film to COC film and back again without having to make significant adjustments to equipment.

A development run on a Klï¿½ckner Medipak CP1200 at a Procter & Gamble pharmaceutical plant in Europe showed COC could be substituted for PVC on high-speed commercial equipment. The plant experienced no issues in forming, sealing, or punching COC blister cards at production speeds of up to 40 cycles per minute.

Additional test runs at a U.S.-based contract packager facility evaluated COC film for a specific blister-packaging application. These tests were conducted on an Uhlmann thermoformer, Model UPS4-MTX. No plug-assist tooling was used.

An initial run sought to understand the commercial feasibility of using 30- ï¿½m/240-ï¿½m/30-ï¿½m (PP/COC/PP). Klï¿½ckner Pentaplastï¿½s Pentapharm COC 240 P/03 film showed that the COC film has forming and sealing temperature ranges of 20ï¿½C each, which are comparable to those typically used for PVC blister packages. In addition, the setup of forming, sealing, and punching stations was the same as with PVC film.

A second set of test runs compared 30-ï¿½m/240-ï¿½m/30-ï¿½m (PP/COC/PP); Klï¿½ckner Pentaplastï¿½s Pentapharm COC 240 P/03 COC film to a 250-ï¿½m Klï¿½ckner Pentaplast M570/01 PVC film. Each film was sealed to a 25-ï¿½m foil having a 15-lb push-through tissue back. Forming temperatures were 140ï¿½, 150ï¿½, and 150ï¿½C in zones 1, 2, and 3 of the machine for the COC and 140ï¿½C throughout for PVC. Sealing temperature was 255ï¿½C for COC and 220ï¿½C for PVC.

The average WVTR of the formed blister was 0.0005 g/pkg/day for COC and 0.0017 g/pkg/day for PVC. Container permeation data were also collected for the COC and PVC blister packages using the USP <671> test method. Both COC and PVC packages were rated Class A, so none exceeded 0.5 mg/day in average blister moisture permeation rate.

Conclusion

Experimental and initial commercial data for COC-based films indicate that they are effective and economic alternatives to PVC films when substantial moisture vapor barrier is needed. These data show that COC films perform well in processing and the final package. They have similar forming and sealing characteristics to PVC films and run on blister packaging equipment without significant issues or equipment modification.

Kurt Trombley, senior packaging engineer, and Becky Frayer, packaging engineer, develop packaging technologies for pharmaceutical applications for Procter & Gamble Pharmaceuticals Inc. They are based in Cincinnati. Ekkehard Beer and Stephen Drost are Topas COC marketing managers for Ticona, the technical polymers business of Celanese AG. They specialize in flexible films for pharmaceutical applications. Beer is based in Kelsterbach, Germany, and Drost is based in Summit, NJ.